(a) Field of the Invention
The invention relates to the formulation and quality control of liquid drug suspensions for oral administration. In particular, the invention relates to methods of formulating liquid suspensions comprising drug-resin complex particles. The invention also relates to methods of confirming the acceptability of drug-resin complex particles for use in formulating liquid drug suspensions. The invention further relates to methods of formulating liquid suspensions in which drug-resin complex particles, the liquid suspension, or both are modified to achieve a desired in vitro dissolution profile. The invention also relates to a novel dissolution method and methods of predicting in vivo bioequivalence based on in vitro dissolution methods.
(b) Description of the Related Art
Sustained Released Liquid Drug Suspensions
Sustained- or prolonged-release dosage forms provide a controlled supply of drug to an organism over an extended period of time. Oral controlled-release drug preparations may provide the convenience of daytime dosing where the dosage form can be administered to an animal first thing in the morning and provide therapeutic levels of the drug throughout the day. Further, an oral controlled-release drug preparation may deliver drugs in a manner that will maintain therapeutically effective plasma levels in an mammal over a period of time that is significantly longer than that which is given by a typical drug dosage form. This eliminates the need to interrupt sleep to take medication and can prevent missed doses, thus improving patient compliance. Benefits obtained from such a controlled release of a specific drug include the control of cough, sleep, enuresis, pain and migraine headaches. Additionally, controlled release of antimicrobials can be used to treat or prevent infection.
Liquid oral dosage forms are known in the art. Liquid formulations have the distinct advantages of dosage flexibility and ease of swallowing. Moreover, there is a recognized need for sustained release formulations to be available in a convenient, easy-to-take liquid dosage form. However, the formulation of liquid oral suspensions having sustained-released capabilities has only resulted in limited success. In part, this is due to the challenges presented in maintaining the stability of sustained-release particles when present in liquid dispersal systems, and the difficulty in achieving sustained release of the drug from the dispersed phase.
Ion-Exchange Drug Resins
Ion-exchange technology has been an approach utilized for achieving sustained release for solid dosage forms and various attempts have been made to further utilize the technology in liquid suspension formulations as well. For example, U.S. Pat. No. 2,990,332 discloses a method of controlling the release rate of drug by adsorbing the salt form of a drug onto a carrier resin such as an ion-exchange resin. However, while complexing drugs on ion-exchange resins has been effective for taste-masking, such uncoated complexes provide only a relatively short delay of drug release and a poor control of drug release, because control of release rate is limited to variation in particle size and cross-linkage of the sulfonic acid-type resin used to prepare the adsorption compounds.
Another approach to prepare liquid suspensions having sustained-released capabilities is by coating drug resins with a water-permeable diffusion barrier. For example, U.S. Pat. No. 4,221,778 discloses a method for preparing products having controlled release properties involving a three-step process: (i) preparation of a drug-resin complex; (ii) treating this complex with a suitable impregnating agent; and (iii) coating the particles of treated complex with a water-permeable diffusion barrier. The impregnation agents are believed to act as humectants to stabilize the size of the swellable particle or minimize rupturing of the water-permeable diffusion barrier, and the barrier coating is believed to delay the release rate of the drug. U.S. Pat. Nos. 4,996,047 and 5,980,882 also provide drug-ion-exchange resin complex particles coated with a water-permeable diffusion barrier layer.
U.S. Pat. No. 4,762,709 discloses a formulation wherein a coated first drug/ion-exchange resin particle is suspended in a liquid carrier with an uncoated second drug/ion-exchange resin component bearing the same charge as the first drug in the coated first drug/ion-exchange resin particle. According to the reference, the release rate of the first drug from the coated first drug/ion-exchange resin particle is increased when the second drug is present in the second uncoated drug/ion-exchange resin complex compared to when the second drug is included with the first drug in the coated first drug/ion-exchange resin.
A product based on this ion-exchange technology is Tussionex® Pennkinetic® Extended-Release Suspension. Tussionex® drug suspension contains hydrocodone polistirex equivalent to 10 mg hydrocodone bitartrate and chlorpheniramine polistirex equivalent to 8 mg chlorpheniramine maleate. Tussionex® drug suspension was approved by the FDA in 1987.
Even though at least one liquid drug ion-exchange system was introduced over 20 years ago, very few products utilizing this technology exist in the market place. This is possibly due to (i) the poor suitability of the ion-exchange resin (i.e., hydrophobicity and swelling); (ii) the complex formulation and manufacturing processes that are required; and (iii) long term stability problems.
As such, there is a need in the art to develop sustained release liquid dosage forms and in particular, liquid dosage forms with better pharmacologic properties and stability that will appeal to the commercial marketplace. In particular, there remains a need for sustained release liquid dosage forms, suitable for once-a-day or twice-a-day administration of drugs.
Drug Development and Manufacturing
Drug development and manufacturing involves many processes including product design, product testing, quality control, and final product formulation. These processes are expensive, laborious, and time-consuming.
As such, there is a need in the art to simplify the processes of drug formulation design and quality control, and it would be useful to reduce the time and cost of performing these processes. In particular, there is also a need to develop quality control methods that ensure batches are efficiently and effectively reproduced. Likewise, there is a need to develop suitable methods for monitoring the effects of adjusting parameters in the development of liquid drug suspensions such as modifying particle size and coating of drug-containing resin particles and for qualifying drug-containing resin particles.